title: Germline PTPRD mutations in Ewing sarcoma: biologic and clinical implications.
abstract: Ewing sarcoma occurs in children, adolescents and young adults. High STAT3 levels have been reported in approximately 50% of patients with Ewing sarcoma, and may be important in tumorigenesis. Protein tyrosine phosphatase delta (PTPRD) is a tumor suppressor that inhibits STAT3 activation. To date, while somatic mutations in PTPRD have been reported in diverse tumors, germline mutations of PTPRD have not been investigated in Ewing sarcoma or other cancers. We identified a novel germline mutation in the PTPRD gene in three of eight patients (37.5%) with metastatic Ewing sarcoma. Although the functional impact in two of the patients is unclear, in one of them the aberration was annotated as a W775stop germline mutation, and would be expected to lead to gene truncation and, hence, loss of the STAT3 dephosphorylation function of PTPRD. Since STAT3 is phosphorylated after being recruited to the insulin growth factor receptor (IGF-1R), suppression of IGF-1R could attenuate the enhanced STAT3 activation expected in the presence of PTPRD mutations. Of interest, two of three patients with germline PTPRD mutations achieved durable complete responses following treatment with IGF-1R monoclonal antibody-based therapies. Our pilot data suggest that PTPRD germline mutations may play a role in the development of Ewing sarcoma, a disease of young people, and their presence may have implications for therapy.
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Jiang
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.forename: Laura S
authors.initials: LS
authors.lastname: Angelo
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Peter M
authors.initials: PM
authors.lastname: Anderson
authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Herzog
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.forename: Robert S
authors.initials: RS
authors.lastname: Benjamin
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000276:immunology; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D017526:Receptor, IGF Type 1; C090899:PTPRD protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2